May 2007
Volume 48, Issue 13
ARVO Annual Meeting Abstract  |   May 2007
Rapid Changes in the Ocular Lens Induced by Dexamethasone: in vivo Rat Study
Author Affiliations & Notes
  • H. P. McNulty
    Elucida Research Company, Beverly, Massachusetts
  • C. M. Doshna
    Pfizer Inc, Groton, Connecticut
  • M. D. Aleo
    Pfizer Inc, Groton, Connecticut
  • J. Byun
    Elucida Research Company, Beverly, Massachusetts
  • C. A. Day
    Elucida Research Company, Beverly, Massachusetts
  • R. P. Mason
    Elucida Research Company, Beverly, Massachusetts
  • R. F. Jacob
    Elucida Research Company, Beverly, Massachusetts
  • Footnotes
    Commercial Relationships H.P. McNulty, None; C.M. Doshna, None; M.D. Aleo, None; J. Byun, None; C.A. Day, None; R.P. Mason, None; R.F. Jacob, None.
  • Footnotes
    Support Pfizer Drug Safety R&D
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 5835. doi:
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    • Get Citation

      H. P. McNulty, C. M. Doshna, M. D. Aleo, J. Byun, C. A. Day, R. P. Mason, R. F. Jacob; Rapid Changes in the Ocular Lens Induced by Dexamethasone: in vivo Rat Study. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5835.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose:: Cataract formation is a well-established side effect of prolonged use of glucocorticoids (GC) in humans, but the mechanism is not well understood. Previous studies of GC-induced cataract formation have been largely limited to in vitro models using animal tissue. In this study, we investigated the in vivo effects of a widely used GC, dexamethasone (DEX), on rat lens lipid composition. Based on these initial results, the direct effect of DEX on lipid peroxidation and structural organization was investigated in parallel in vitro experiments using model membrane systems.

Methods:: Eight male Sprague Dawley-derived rats (8 weeks old) were divided into two groups and injected with DEX (50 mg/kg/day, i.p.) or corn oil for 4 days. Lenses from each group were excised ~25 hr after final administration of drug or vehicle and the lens lipids were extracted with methanol using ultrasonification. The extracts were then subjected to infrared spectroscopic analysis. In separate experiments the effects of DEX on the rate of lipid peroxidation and lipid organization were evaluated in model membranes consisting of cholesterol and diarachidonoylphosphatidylcholine using spectrophotometric and small angle x-ray diffraction techniques, respectively.

Results:: Lens methanol extracts contained primarily phospholipid with small quantities of protein. Compared to control, DEX induced consistent and significant spectral changes in the lens following only 4 days of administration of drug, although no visible signs of cataract formation in vivo were observed. These spectral shifts could be attributed to alterations in protein and/or an increase in lipid peroxidation. In model membrane studies, DEX increased lipid peroxidation and induced cholesterol domain formation compared to controls.

Conclusions:: This study demonstrated that DEX may contribute to cataractogenesis via two possible mechanisms: (1) by altering lens protein and/or (2) by inducing lipid peroxidation. This hypothesis is supported by results obtained in model membrane systems where DEX promoted lipid peroxidation and subsequent cholesterol domain formation.

Keywords: drug toxicity/drug effects • lipids • oxidation/oxidative or free radical damage 

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